Immunology plays an important role in understanding and diagnosis of disease and further it is the most rapidly developing area of biomedical research for the prevention and treatment of a wide range of disorders. Arthritis. ulcerative colitis, asthma, allergic reactions, parasitic and infectious diseases are now primarily considered to be immunological disorders. Immune mechanisms are also involved in a variety of other diseases such as diabetes mellitus, cancer, myocardial diseases, cirrhosis and atherosclerosis.
The modulation of immune response by using a variety of agents in order to alleviate the disease has been of interest since many years and the first authentic experimental report on immunomodulation was made by Lazarev in 1947 in which he effectively demonstrated the capacity of diabazol to increase non-specific resistance. This activity was termed as adaptogenic.
The non-specific immunity is provided by granulocytes, macrophages, natural killer cells, complement and properdin, and the various effector substances including interleukins, tumour necrosis factor, interferons, lysozymes, prostaglandins, oxygen radicals and other mediators. From the evolutionary angle, this non-specific immunity is more primitive, because it responds immediately without any initial latent period and it does not have immunological memory.
The inflammatory and allergic manifestations in the living cell are thought to be the direct cause of hyperactivity of immune function entities in non-specific immunity, whereas the the suppression or deficiency of immune functions are the result of hypoactivity. The functioning and efficiency of non-specific immunity may be influenced by many exogenous and endogeneous factors like physical and psychological stress, hormonal imbalance, pharmaceuticals and the like.
`Immunomodulation` is any procedure which can alter non specific immunity by interfering with its functioning. If it results in enhancement of immune reactions, it results in immunostimulation and primarily implies stimulation of the non specific immunity, that is stimulation of the function and efficiency of granulocytes, macrophages, natural killer cells, complement and properdin, and the various effector substances including interleukins, tumour necrosis factor, interferons, lysozymes prostaglandins, oxygen radicals and other mediators. Immunosuppression mainly implies reduced resistance against infections and stress and may be due to environmental or chemotherapeutic factors.
Immunostimulation and immunosuppression both need to be addressed in order to regulate normal immunological functioning. Hence, immunostimulating and immunosuppressing agents both have their own standing. There are a variety of known immunosuppressing agents, for instance cyclosporin, however few immunostimulating agents are available. Apart from specific stimulative or suppressive activity, it is believed that certain agents of plant origin have the activity to normalize or modulate pathophysiological processes in the underlying immune response and hence the term immunomodulation or immunomodulatory agents are used for these agents. This activity is believed to be dose dependant as can be seen from the immunostimulation at low dilutions of many immunosuppressants.
Most of the chemical agents known to have effect on the immune system are immunosuppressants and cytotoxic agents. For instance, Azathioprine inhibits DNA synthesis, Cyclophosphamide is relatively selective for lymphoid tissue. Cyclosporin A has applications in organ transplantations, thiocarbomate has direct cytotoxic effects. Many chemotherapeutic agents available today are basically immunosuppresants, most of them are cytotoxic and exert a variety of side effects. Further, the metabolism and clinical safety of these agents has also not been clearly established. On the other hand there are reasons to believe that plant extracts having pharmacologically and biologically activity can serve as a good source for newer immunostimulants. Brekman et al have studied a large number of folk medicines from different parts of the world and these are reviewed in the Annual Review of Pharmacology, 1969.
Plants having pharmacological and biological activity have been the basis of treatment of human diseases from time immemorial. Every country in the world has lists of herbal remedies for the treatment of diseases and various human conditions. The foundations of the modern drug industry are practically based on the inventions of active compounds from plants which have been developed further synthetically to obtain more suitable analogues. For example the isolation of morphine from opium poppy by Fredric Serterner, Quinine from the cinchona tree, cocaine from the leaves of Coca shrubs, and a host of drugs such as atropine, curate, digoxin, reserpine and the like.
There are reasons to believe that most of the plants used in the past for critical research for developing new drugs are mainly of a poisonous nature. This, it is believed, has happened because of two primary reasons. Firstly, the lack of knowledge in selecting correct plants having medical activity and not being poisonous and lack of know-how of the required technology in drug research. It is relatively easy to identify a poisonous plant in the forests. It is extremely difficult to identify non-poisonous plants having truly medicinal properties. To determine the poisonous character of a plant a few generation studies are often adequate. The identification of medicinal activity of a plant needs studies spread over a large number of generations.
In India, Ayurveda, has carried out these studies for many generations and has recorded the medicinal uses of specific plants for over 5000 years or even more. These records are valuable, since effectively these medicines have been tested for centuries on millions of people. It is suggested that the plant extracts identified in the present invention with potential immunomodulatory activity along with other supportive activity will provide short and long term benefits to patients having immunopathological disorders such as rheumatic diseases and degenerative diseases of the musculoskeletal system, such as osteoarthritis.
This invention relates to a process for obtaining a pharmacologically or biologically active plant extract substantially as it occurs in its natural state suitable for converting in a convenient administrable dosage form.
Use of pharmacologically or biologically active plant extracts is well-known. It is also known that the biologically or pharmacologically active compounds can be isolated and purified from the plant extract to obtain therapeutic compositions.
According to drug-receptor theory, the compatibility of the structure of a drug with the receptor, is considered to be most important for determining the maximal or optimal activity of any drug. Following this principle, most of the modern drugs have been invented by synthetic modification of active molecules from natural or other sources by following Hanch Analysis and QSAR studies. Such drug-receptor interaction can also be studied non on CADD by artificial simulation and thus discovering the best possible structure for maximum activity. In this exercise, a large number of structural analogues are needed to be synthesized and further tested for pharmacologically or biologically activity or bio-activity. The main purpose of this exercise is to determine the most suitable structure for maximum activity.
Most drugs which have developed from such exercises are not completely compatible with the requirements of the receptor site. Thus they have limitations in therapeutic management and simultaneously exhibit toxic effects. Synthetic synthesis and purification processes have not been able to emulate the pharmacologically or biologically activity of natural substances such as atropine, digitalis, reserpine, nicotine and the like.
Naturally occurring plant material contain a series of closely-related compounds produced naturally via biological and biochemical reactions. The plant is capable of producing a wide range of analogues at least one of which possesses the desired receptor compatibility. However, the related compounds appear to exercise a synergistic effect on the pharmacologically or biologically activity of the compatible compound and at the same time suppress toxic effects. However, a major drawback in using plant material in its crude form, is that the dosages required of such material, to be therapeutically beneficial, are quite high, sometimes even upto 10 gms a day or more. Such quantities cannot be conveniently converted into suitable dosage forms.
This invention, therefore, seeks to disclose a process for obtaining a pharmacologically or biologically active plant extract substantially as it occurs in its natural state suitable for converting in a convenient administrable dosage form.
The process according to this invention, seeks to provide a beneficiated plant extract, in which the plant extract comprises all pharmacologically or biologically active chemicals in their original natural state and proportions.
Thereby, the advantage of naturally occurring series and analogues of compounds is achieved without compromising the overall effects of these compounds.
This invention specifically relates to a pharmaceutical synergistic composition for the treatment of rheumatic diseases and degenerative diseases of the musculo-skeletal system. Note specifically for the treatment of rheumatoid arthritis and osteoarthritis.
Arthritis is a common progressive disease of various etiologies. Common symptoms include pain and inflammation of one or more joints.
Rheumatoid arthritis is a chronic syndrome characterised by non-specific usually symmetric inflammation of the peripheral joints, potentially resulting in progressive destruction of articular and periarticular structures leading to deformity. There is a wide spectrum of disease severity but many patients run a course of intermittent relapses and remissions with an overall pattern of slowly progressive joint destruction and deformity. Persistent inflammation produces symptoms and damages tissue causing loss of cartilage, erosion of bone matter and subluxation of joint. This results in a high degree of morbidity resulting in disturbed daily life of the patient.
The etiology of this debilitating disease is unknown, however it is considered to be immmuno pathalogical in origin. It is believed to be the result of the presence of a relevant antigen to an immunogenetically susceptible host. Presence of rheumatoid factor in blood, increase in the erythrocyte sedimentation rate and induced radiological changes are used for classification and correct diagnosis.
Present treatment of Rheumatoid Arthritis includes first line drugs for control of pain and inflammation classified as non-steroidal, anti-inflammatory drugs (NSAIDS). Secondary treatment include corticosteroids, slow acting antirheumatic drugs (SAARDS) or disease modifying (DM) drugs include penicillinamine like drugs such as cyclophosphamide, methotrexate, gold salts, azothioprine, levamisole and the like. All these drugs have severe side effects and most of them are cytotoxic.
Out of the aforesaid drugs, only levamisole can be categorised as immunostimulatory and has been reported to reduce rheumatoid factor titers.
The drugs used at present have limited advantages and their effects mainly of short term duration and there are many disadvantages in the use of these drugs over extended periods of time. Further the drugs used at present are costly and have low benefit-risk ratio. The ideal compound to modify the progress of the disease has not yet been found hithertofore.
The usefulness of immunmodulatory drugs in the treatment rheumatoid arthritis is based on the following evidences for immunopathalogical disorders in this disease. The disease is primarily an inflammation of joints in which the synovium is expanded by an infiltrate of cells--Lymphocytes; plasma cells and a variety of other cells, mostly mononuclear cells; the joint fluid is rich in polymorphoneuclear leucocytes; and the cartilage is destroyed by the advancing edge of synovial connective tissue called panus. Rheumatoid Arthritis is therefore a chronic multisystem disease of unknown etiology characterized chiefly by persistent inflammatory synovitis, usually involving peripheral joints in a symmetrical fashion. Cartilaginous destruction, bony erosions, and joint deformation are hallmarks of persistent synovial inflammation. Pathogenesis is not well understood; synovial hyperboles and hypertrophy, lymphocytic infiltration of synovial tissue, joint infiltration by neutrophils, protease release, and chondrocyte activation occur. Free radical damage is also believed to be the important factor in its pathophysiology.
The clinical manifestations include symmetrical polyarthritis of peripheral joints with pain, tenderness, and swelling of affected joints; morning stiffness is common; PIP and MCP joints frequently involved; joint deformities may develop after persistent inflammation. Extra-articular manifestations include rheumatoid nodules, rheumatoid vasculitis, pleuropulmonary inflammations, scleritis, sicca syndrome, Felty's syndrome (splenomegaly and neutropenia) osteoporosis.
It is believed that rheumatoid arthritis results from the presentation of a relevant antigen to an immunogenetically susceptible host. The antigens that could potentially initiate an immune response that results in rheumatoid arthritis might be endogeneous or exogeneous. Possible endogeneous antigens include collagen, mucopolysaccharides and rheumatoid factors. Exogeneous antigens include mycoplasms, mycobacteria, spirochytes and viruses. The Epstein-Barr virus has received the most attention as a possible cause of rheumatoid arthritis.
This invention also relates to a process of obtaining beneficiated biologically active extracts obtained from the following naturally occurring plant species: ASHWAGANDHA (Withania somnifera), SALLAI GUGGUL (Boswellia serrata), TURMERIC (Curcuma longa), GINGER (Zingiber officinale) for use in a composition for the treatment of rheumatoid arthritis and osteoarthritis.